Biodegradable synthetic polymers offer a number of advantages over other materials in various biological applications including bone and cartilage repair. For example, in relation to the development of scaffolds in tissue engineering, the key advantages include the ability to tailor mechanical properties and degradation kinetics to suit various applications. Synthetic polymers are also attractive in tissue engineering applications because they can be fabricated into various shapes with desired pore morphologic features conducive to tissue in growth. Furthermore, polymers can be designed with chemical functional groups that can, for example, induce tissue in-growth, or be utilised to adapt the polymers to the application in question.
A vast majority of biodegradable polymers studied belong to the polyester family. Among these poly(α-hydroxy acids) such as poly(glycolic acid), poly(lactic acid) and a range of their copolymers have historically comprised the bulk of published material on biodegradable polyesters and has a long history of use as synthetic biodegradable materials1-3 in a number of clinical applications. Among these applications, poly(glycolic acid), poly(lactic acid) and their copolymers, poly-p-dioxanone, and copolymers of trimethylene carbonate and glycolide have been the most widely used. The major applications include resorbable sutures, drug delivery systems and orthopedic fixation devices such as pins, rods and screws4-5. Among the families of synthetic polymers, the polyesters have been attractive for these applications because of their ease of degradation by hydrolysis of ester linkage, degradation products are resorbed through the metabolic pathways in some cases and the potential to tailor the structure to alter degradation rates.
The recent interest in finding tissue-engineered solutions to repair damaged tissues and organs due to injuries/diseases has made necessary the development of new degradable polymers that meet a number of demanding requirements. These requirements range from the ability of the polymer scaffold to provide mechanical support during tissue growth and gradually degrade to biocompatible products to more demanding requirements such as the ability to incorporate cells, growth factors etc and provide cell-conductive and inductive environments. Many of the currently available degradable polymers do not meet all of these requirements. Furthermore, the development of in-situ polymerizable compositions that can function as cell delivery systems in the form of an injectable liquid/paste are becoming increasingly attractive in tissue engineering applications.
Scaffolds made from synthetic and natural polymers, and ceramics have been investigated extensively for orthopedic repair6. This approach has advantages such as the ability to generate desired pore structures and the ability to match size, shape and mechanical properties to suit a variety of applications. However, shaping these scaffolds to fit cavities or defects with complicated geometries, bonding to the bone tissues, and incorporating cells and growth factors, and the requirements of open surgery are a few major disadvantages of the use of known scaffold materials.
The synthetic polymers used in fabricating scaffolds for growing cells belong to the poly(ester family). For example, poly(glycolic acid) and poly(lactic acid) have been the most commonly used polymers because of their relative ease of degradation under hydrolytic conditions and the degradation products are resorbed to the body. However, these polymers have a number of disadvantages, including rapid loss of mechanical properties, difficulty in processing, and the acidity of degradation products resulting in tissue necrosis7.
Development of a degradable polymer composition that is ideally flowable and could be injected to fill a defect or cavity has number of advantages. A major advantage would be the possibility of administering a gel arthroscopically in tissue engineering applications avoiding surgery in many cases. Such a polymer would also have the advantage of filling cavities with complex geometries, and of providing good bonding to bone tissue. Incorporation of cells, growth factors and other components to support cell growth could also be incorporated with a gel. Such polymer systems also have the potential to be formulated to generate porous structure upon curing to facilitate nutrient flow to cells during growth and proliferation. Further, such systems may be useful in pre-fabricating scaffolds with complex shapes having appropriate pore structures with biological components already incorporated.
Injectable polymer compositions based on ceramic and synthetic polymers have been reported. Ceramic materials such as calcium phosphate cements have the disadvantage of very slow degradation, which in tissue engineering applications leads to decreased tissue regeneration at the site of the implant, and poor mechanical properties6. To overcome some of these problems, injectable compositions based on poly(anhydrides) and poly(propylene fumarate) have been developed. The general method employed includes the preparation of polymerisable precursors with hydrolyzable functional groups in the backbone and curing by free-radical means using either chemical or photo initiation. For example, Mikos and coworkers8 have developed poly(propylene fumarate) based injectable systems by incorporating mineral fillers to improve mechanical strength. Similarly, Photo-cross-linkable poly(anhydrides) has also been developed for use in orthopedic applications, particularly focusing on achieving high mechanical strength. The systems developed are based on dimethacrylated anhydrides9. Both systems require high level of initiators as well as promoters to achieve short curing times. These polymer compositions generally have poor compressive strengths and often require the incorporation of fillers to improve mechanical strength. Photo-curable systems also have the limitation of incomplete curing, particularly in thick samples due to poor light penetration. Further, the above polymer systems have limitations in terms of the options available for tailoring properties for different applications.
Over the last three decades the use of polyurethanes has been explored in biomedical applications due to their excellent mechanical properties and great chemical versatility. Many years of research have resulted in the development of biostable polyurethanes useful for a range of long-term medical implants10.
Several research groups have reported on preparation and properties of biodegradable polyurethanes based on a range of polyester polyols. Bruin et al11 reported on the synthesis of biodegradable poly(ester-urethae) elastomer networks by cross-linking star branched L-lactide and glycolide-ε-caprolactone copolymers with ethyl 2,6-diisocyanato hexane (LDI). Saad and coworkers12-13 reported biodegradable, elastic and highly porous scaffolds based on poly (3-hydroxybutric acid) and poly(caprolactone-co-diethylene glycol) polyols with aliphatic diisocyanates. Bennett et al14 disclosed polymers useful for surgical devices, based on star polymers of soft segment forming monomers, which can be cross-linked with isocyanates.
Zang et al15 have described lysine diisocyanate, glycerol and water based biodegradable spongy polyurethanes that may be useful for biomedical applications as suggested based on in-vitro test results. Story et al16-19 report on the preparation of hydrolysable poly(ester networks) from L-lysine diisocyanate and D,L-lactide/ε-caprolactone home—and copolyester triols and trimethylene carbonate homoployester and copolyester triols. In these studies hydroxy functional polyester triols were reacted with diisocyanates such as lysine diisocyanate and toluene diisocyanate to form network polyurethanes. Likewise, Bruin et al20 have reported on biodegradable polyurethanes networks based on LDI and poly(glycolide-co-ε-caprolactone) for fabrication of 2-layer artificial skin.
Spaans et al21-23 discloses biomedical polyurethane-amides from isocyanate-terminated polyester networks by reacting with dicarboxylic acid or hydroxycarboxylic acid in the presence of sodium chloride crystals to produce macroporous structures suitable for repairing meniscal lesion. Similarly, van Tienen et al24 reported on the caprolactone/L-lactide based polyurethane networks, fabricated to from porous scaffolds useful for repair of knee meniscus defects.
Woodhouse et al25 have disclosed a biodegradable polyurethane material having a backbone containing at least one amino acid group suitable for wound dressings.
Notwithstanding the wide reporting of degradable polyurethanes in the literature, there has been relatively little research directed to the development of degradable polyurethanes structurally tailored to be biodegradable for tissue engineering. As a class of synthetic polymers, polyurethanes offer numerous opportunities to tailor materials with properties and chemical composition to suit applications in soft tissue as well as hard tissue engineering applications. Several research papers describe polyurethanes with degradable polyester soft segments and methods to fabricate porous scaffolds that support cell-growth. However, there are no reports on degradable polyurethane-based and desirably injectable polymer systems that can incorporate cells, growth factors and other components to support cell growth as well or on curing such polymer compositions with low heat generation to minimize cell necrosis.
Accordingly, it is an object of the present invention to provide biodegradable, biocompatible polymers that are capable of supporting living and non living biological additives during preparation and use and which are flowable, and preferably injectable. It is a further object to provide prepolymer compositions that may be cured with degradable oligomers ex vivo or in vivo to form the biocompatible, biodegradable polymers useful as scaffolds for tissue engineering.
These polymer prepared will desirably be capable of incorporating biological components such as cells, growth factors, and other components such as nano-particle hydroxyapatite, calcium phosphate and other particles and can be cured in vivo or ex vivo to form solid, porous scaffolds for biomedical applications.